The purpose of this PPG renewal application is to enable scientists at the San Diego VA Hospital, UCSD and The Salk Institute to maintain an efficient, interactive and mutually reinforcing program of basic and translational research focusing on the effects of adenylyl cyclase type VI (ACVI), a pivotal effector molecule, in failing heart. Strengths of our Program include the breadth of expertise and novelty of approaches ranging from basic science to translational studies and clinical gene transfer. We propose to complete clinical gene transfer studies in patients with severe congestive heart failure (CHF), and perform mechanistic studies on the effects of AC expression on fibroblast function, the cardiac interstitium and transcriptional regulation in the heart. The proposed Program will provide a mechanism to identify and refine communal research goals, develop effective experimental approaches, share advanced technology and implement effective translational studies that already have culminated in potential clinical therapies. Understanding how AC favorably affects heart function will require studies in animal models of CHF and cardiac fibrosis using modern genetic tools, examination of signaling pathways, cellular imaging, and studies of transcriptional regulation. The Program will include three Projects: Project 1 (Dr. Hammond) will complete a clinical trial of intracoronary delivery of ACVI in patients with CHF, and develop and test a regulated expression vector for a Phase 2 clinical trial. Project 2 (Dr. Insel) will focus on the impact of increased AC expression on the cardiac interstitium in studies of cardiac fibroblasts, using cellular and molecular approaches to study signaling pathways involved in proliferation, differentiation and functional activity of cardiac fibroblasts. Project 3 (Dr. Montminy) will focus on the impact of cardiac AC expression on transcriptional regulation using murine models expressing loss or gain of function CREB alleles (including mice with cardiac-directed AC expression or deletions of AC) to investigate the importance of this pathway in cardiac function. Four Cores will support the Program: Digital Imaging (Dr. Feramisco);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Roth) and Clinical &Administrative (Dr. Hammond).